Pocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site
Pocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site
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DOI：
10.1038/s41467-019-08965-w
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发表时间：
2019-03-04
影响因子：
16.6
通讯作者：
Altman, Russ B.
中科院分区：
文献类型：
--
作者：
Lo, Yu-Chen;Cormier, Olga;Altman, Russ B.
紫杉烷是一类具有广谱抗癌活性的天然产物。这种活性是通过与β-微管蛋白的紫杉烷位置相互作用而调节的，从而导致微管稳定和细胞死亡。现有的紫杉烷类药物包括紫杉醇和第二代多西紫杉醇，虽然广泛用于乳腺癌和其他恶性肿瘤的治疗，但目前仍受到严重不良反应和剂量限制毒性的限制。为了发现紫杉烷位点调节剂，我们使用了来自PDB的14,000个类药物口袋的计算结合位点相似性筛选，揭示了雌激素受体和β-微管蛋白紫杉烷结合口袋之间出人意料的相似之处。通过细胞和生化分析对9种选择性雌激素受体调节剂(SERM)的评价证实了紫杉烷的位置相互作用、微管稳定和细胞增殖抑制。我们的研究表明，SERM可以调节微管组装，并增加了抑制细胞增殖的雌激素受体非依赖性机制的可能性。
Taxanes are a family of natural products with a broad spectrum of anticancer activity. This activity is mediated by interaction with the taxane site of beta-tubulin, leading to microtubule stabilization and cell death. Although widely used in the treatment of breast cancer and other malignancies, existing taxane-based therapies including paclitaxel and the second-generation docetaxel are currently limited by severe adverse effects and dose-limiting toxicity. To discover taxane site modulators, we employ a computational binding site similarity screen of >14,000 drug-like pockets from PDB, revealing an unexpected similarity between the estrogen receptor and the beta-tubulin taxane binding pocket. Evaluation of nine selective estrogen receptor modulators (SERMs) via cellular and biochemical assays confirms taxane site interaction, microtubule stabilization, and cell proliferation inhibition. Our study demonstrates that SERMs can modulate microtubule assembly and raises the possibility of an estrogen receptor-independent mechanism for inhibiting cell proliferation.